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2.
Nature ; 610(7933): S48-S49, 2022 10.
Article in English | MEDLINE | ID: covidwho-2096650
3.
Nature ; 610(7933): S42-S44, 2022 10.
Article in English | MEDLINE | ID: covidwho-2096648
4.
iScience ; 25(12): 105507, 2022 Dec 22.
Article in English | MEDLINE | ID: covidwho-2095533

ABSTRACT

Here we interrogate the factors responsible for SARS-CoV-2 breakthrough infections in a K18-hACE2 transgenic mouse model. We show that Delta and the closely related Kappa variant cause viral pneumonia and severe lung lesions in K18-hACE2 mice. Human COVID-19 mRNA post-vaccination sera after the 2nd dose are significantly less efficient in neutralizing Delta/Kappa than early 614G virus in vitro and in vivo. By 5 months post-vaccination, ≥50% of donors lack detectable neutralizing antibodies against Delta and Kappa and all mice receiving 5-month post-vaccination sera die after the lethal challenges. Although a 3rd vaccine dose can boost antibody neutralization against Delta in vitro and in vivo, the mean log neutralization titers against the latest Omicron subvariants are 1/3-1/2 of those against the original 614D virus. Our results suggest that enhanced virulence, greater immune evasion, and waning of vaccine-elicited protection account for SARS-CoV-2 variants caused breakthrough infections.

5.
iScience ; 25(12): 105475, 2022 Dec 22.
Article in English | MEDLINE | ID: covidwho-2095531

ABSTRACT

Recently, a new variant lineage of SARS-CoV-2, namely Omicron, became the dominant global circulating strain. The multiple antigenic mutations of Omicron largely decrease the efficiency of current vaccines and neutralizing antibodies, which highlights the need for more potent and reachable medical countermeasures. Here, we hypothesize that direct viral clearance by nasal irrigation might be a convenient and alternative option, and perform proof-of-concept experiments in the Syrian hamster model. Interestingly, Omicron shows a different dynamic in the changes of viral RNA, viral titers, and proinflammatory cytokines in nasal rinsing samples when compared with the prototype. Meanwhile, the levels of viral load and proinflammatory cytokines in nasal rinsing samples can indicate the severity of lung injury. Of note, daily nasal irrigation efficiently attenuates inflammation and lung injury in Omicron-infected hamsters by decreasing the viral loads in the respiratory tract organs. Moreover, daily nasal irrigation effectively suppresses viral transmission by close contact.

6.
iScience ; : 105365, 2022 Nov 01.
Article in English | MEDLINE | ID: covidwho-2095530

ABSTRACT

Potent and biostable inhibitors of the main protease (Mpro) of SARS-CoV-2 were designed and synthesized based on an active hit compound 5h (2). Our strategy was based not only on the introduction of fluorine atoms into the inhibitor molecule for an increase of binding affinity for the pocket of Mpro and cell membrane permeability but also on the replacement of the digestible amide bond by a surrogate structure to increase the biostability of the compounds. Compound 3 is highly potent and blocks SARS-CoV-2 infection in vitro without a viral breakthrough. The derivatives, which contain a thioamide surrogate in the P2-P1 amide bond of these compounds (2 and 3), showed remarkably preferable pharmacokinetics in mice compared with the corresponding parent compounds. These data show that compounds 3 and its biostable derivative 4 are potential drugs for treating COVID-19 and that replacement of the digestible amide bond by its thioamide surrogate structure is an effective method.

10.
iScience ; 25(11): 105455, 2022 Nov 18.
Article in English | MEDLINE | ID: covidwho-2086329

ABSTRACT

Mass vaccination campaigns reduced COVID-19 incidence and severity. Here, we evaluated the immune responses developed in SARS-CoV-2-uninfected patients with predominantly antibody-deficiencies (PAD) after three mRNA-1273 vaccine doses. PAD patients were classified based on their immunodeficiency: unclassified primary antibody-deficiency (unPAD, n = 9), common variable immunodeficiency (CVID, n = 12), combined immunodeficiency (CID, n = 1), and thymoma with immunodeficiency (TID, n = 1). unPAD patients and healthy controls (HCs, n = 10) developed similar vaccine-induced humoral responses after two doses. However, CVID patients showed reduced binding and neutralizing titers compared to HCs. Of interest, these PAD groups showed lower levels of Spike-specific IFN-γ-producing cells. CVID individuals also presented diminished CD8+T cells. CID and TID patients developed cellular but not humoral responses. Although the third vaccine dose boosted humoral responses in most PAD patients, it had limited effect on expanding cellular immunity. Vaccine-induced immune responses in PAD individuals are heterogeneous, and should be immunomonitored to define a personalized therapeutic strategies.

11.
iScience ; 25(11): 105438, 2022 Nov 18.
Article in English | MEDLINE | ID: covidwho-2083129

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a rapidly evolving RNA virus that mutates within hosts and exists as viral quasispecies. Here, we evaluated the within-host diversity among vaccinated and unvaccinated individuals (n = 379) infected with different SARS-CoV-2 Variants of Concern. The majority of samples harbored less than 14 intra-host single-nucleotide variants (iSNVs). A deep analysis revealed a significantly higher intra-host diversity in Omicron samples than in other variants (p value < 0.05). Vaccination status and type had a limited impact on intra-host diversity except for Beta-B.1.315 and Delta-B.1.617.2 vaccinees, who exhibited higher diversity than unvaccinated individuals (p values: <0.0001 and <0.0021, respectively). Three immune-escape mutations were identified: S255F in Delta and R346K and T376A in Omicron-B.1.1.529. The latter 2 mutations were fixed in BA.1 and BA.2 genomes, respectively. Overall, the relatively higher intra-host diversity among vaccinated individuals and the detection of immune-escape mutations, despite being rare, suggest a potential vaccine-induced immune pressure in vaccinated individuals.

12.
iScience ; 25(11): 105412, 2022 Nov 18.
Article in English | MEDLINE | ID: covidwho-2083114

ABSTRACT

Live-attenuated vaccines are generally highly effective. Here, we aimed to develop one against SARS-CoV-2, based on the identification of three types of temperature-sensitive (TS) strains with mutations in nonstructural proteins (nsp), impaired proliferation at 37°C-39°C, and the capacity to induce protective immunity in Syrian hamsters. To develop a live-attenuated vaccine, we generated a virus that combined all these TS-associated mutations (rTS-all), which showed a robust TS phenotype in vitro and high attenuation in vivo. The vaccine induced an effective cross-reactive immune response and protected hamsters against homologous or heterologous viral challenges. Importantly, rTS-all rarely reverted to the wild-type phenotype. By combining these mutations with an Omicron spike protein to construct a recombinant virus, protection against the Omicron strain was obtained. We show that immediate and effective live-attenuated vaccine candidates against SARS-CoV-2 variants may be developed using rTS-all as a backbone to incorporate the spike protein of the variants.

13.
iScience ; 25(11): 105427, 2022 Nov 18.
Article in English | MEDLINE | ID: covidwho-2082887

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused an epidemic and spread rapidly all over the world. Because the analysis of host factors other than receptors and proteases has not been sufficiently performed, we attempted to identify and characterize host factors essential for SARS-CoV-2 infection using iPS cells and airway organoids (AO). Based on previous CRISPR screening and RNA-seq data, we found that exocyst complex component 2 (EXOC2) is one important host factor for SARS-CoV-2 infection. The intracellular SARS-CoV-2 nucleocapsid (N) expression level was decreased to 3.7% and the virus copy number in cell culture medium was decreased to 1.6% by EXOC2 knockdown. Consistently, immunostaining results showed that N protein-positive cells were significantly decreased by EXOC2 knockdown. We also found that EXOC2 knockdown downregulates SARS-CoV-2 infection by regulating IFNW1 expression. In conclusion, controlling the EXOC2 expression level may prevent SARS-CoV-2 infection and deserves further study.

14.
Bioessays ; 42(10): e2000091, 2020 10.
Article in English | MEDLINE | ID: covidwho-2074923

ABSTRACT

Despite claims from prominent scientists that SARS-CoV-2 indubitably emerged naturally, the etiology of this novel coronavirus remains a pressing and open question: Without knowing the true nature of a disease, it is impossible for clinicians to appropriately shape their care, for policy-makers to correctly gauge the nature and extent of the threat, and for the public to appropriately modify their behavior. Unless the intermediate host necessary for completing a natural zoonotic jump is identified, the dual-use gain-of-function research practice of viral serial passage should be considered a viable route by which the novel coronavirus arose. The practice of serial passage mimics a natural zoonotic jump, and offers explanations for SARS-CoV-2's distinctive spike-protein region and its unexpectedly high affinity for angiotensin converting enzyme (ACE2), as well as the notable polybasic furin cleavage site within it. Additional molecular clues raise further questions, all of which warrant full investigation into the novel coronavirus's origins and a re-examination of the risks and rewards of dual-use gain-of-function research.


Subject(s)
Betacoronavirus/genetics , Coronavirus Infections/etiology , Coronavirus Infections/transmission , Pneumonia, Viral/etiology , Pneumonia, Viral/transmission , Zoonoses/transmission , Amino Acid Sequence , Angiotensin-Converting Enzyme 2 , Animals , Betacoronavirus/growth & development , COVID-19 , Gain of Function Mutation/genetics , Humans , Pandemics , Peptidyl-Dipeptidase A/metabolism , Protein Binding , SARS-CoV-2 , Serial Passage , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/metabolism , Zoonoses/virology
15.
iScience ; 25(11): 105394, 2022 Nov 18.
Article in English | MEDLINE | ID: covidwho-2076217

ABSTRACT

Swine acute diarrhea syndrome coronavirus (SADS-CoV) is an enveloped, single-stranded, positive-sense RNA virus belonging to the Coronaviridae family. Increasingly studies have demonstrated that viruses could utilize autophagy to promote their own replication. However, the relationship between SADS-CoV and autophagy remains unknown. Here, we reported that SADS-CoV infection-induced autophagy and pharmacologically increased autophagy were conducive to viral proliferation. Conversely, suppression of autophagy by pharmacological inhibitors or knockdown of autophagy-related protein impeded viral replication. Furthermore, we demonstrated the underlying mechanism by which SADS-CoV triggered autophagy through the inactivation of the Akt/mTOR pathway. Importantly, we identified integrin α3 (ITGA3) as a potential antiviral target upstream of Akt/mTOR and autophagy pathways. Knockdown of ITGA3 enhanced autophagy and consequently increased the replication of SADS-CoV. Collectively, our studies revealed a novel mechanism that SADS-CoV-induced autophagy to facilitate its proliferation via Akt/mTOR pathway and found that ITGA3 was an effective antiviral factor for suppressing viral infection.

16.
iScience ; 25(11): 105379, 2022 Nov 18.
Article in English | MEDLINE | ID: covidwho-2069211

ABSTRACT

The emergence of SARS-CoV-2 variants raises concerns of reduced COVID-19 vaccine efficacy. We investigated the humoral immunity in uninfected and previously infected ChAdOx1 nCoV-19, BNT162b2 and CoronaVac vaccinees, who have received complete regimes of vaccines by means of a SARS-CoV-2 surrogate virus blocking test. The ChAdOx1 nCoV-19 (p = 0.0013) and BNT162b2 (p = 0.0005) vaccines induced significant higher blocking activity with longer durability against the Spike (S) protein receptor binding domain (RBD) of wild type SARS-CoV-2 than the CoronaVac vaccine in uninfected vaccinees. Prior infection improved protection in the CoronaVac vaccinees. Subsequent investigation on the breadth of SARS-CoV-2 vaccine-induced antibody blocking responses, revealed that all vaccine platforms cross-protected uninfected vaccinees against all variant of concerns, except Omicron. Prior infection protected the ChAdOx1 nCoV-19 and BNT162b2 vaccinees against Omicron but not CoronaVac vaccinees. Our study suggests that vaccines that induce broader sterilizing immunity are essential to fight against fast-emerging variants.

17.
iScience ; 25(11): 105369, 2022 Nov 18.
Article in English | MEDLINE | ID: covidwho-2069210

ABSTRACT

Omicron is currently the dominant SARS-CoV-2 variant and several sublineages have emerged. Questions remain about the impact of previous SARS-CoV-2 exposure on cross-variant immune responses elicited by the SARS-CoV-2 Omicron sublineage BA.2 compared to BA.1. Here we show that without previous history of COVID-19, BA.2 infection induces a reduced immune response against all variants of concern (VOC) compared to BA.1 infection. The absence of ACE2 binding in sera of previously naïve BA.1 and BA.2 patients indicates a lack of meaningful neutralization. In contrast, anti-spike antibody levels and neutralizing activity greatly increased in the BA.1 and BA.2 patients with a previous history of COVID-19. Transcriptome analyses of peripheral immune cells showed significant differences in immune response and specific antibody generation between BA.1 and BA.2 patients as well as significant differences in the expression of specific immune genes. In summary, prior infection status significantly impacts the innate and adaptive immune response against VOC following BA.2 infection.

18.
iScience ; 25(11): 105348, 2022 Nov 18.
Article in English | MEDLINE | ID: covidwho-2069208

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the pathogen of coronavirus disease 2019 (COVID-19), has infected hundreds of millions of people and caused millions of deaths. Looking for valid druggable targets with minimal side effects for the treatment of COVID-19 remains critical. After discovering host genes from multiscale omics data, we developed an end-to-end network method to investigate drug-host gene(s)-coronavirus (CoV) paths and the mechanism of action between the drug and the host factor in a directional network. We also inspected the potential side effect of the candidate drug on several common comorbidities. We established a catalog of host genes associated with three CoVs. Rule-based prioritization yielded 29 Food and Drug Administration (FDA)-approved drugs via accounting for the effects of drugs on CoVs, comorbidities, and drug-target confidence information. Seven drugs are currently undergoing clinical trials as COVID-19 treatment. This catalog of druggable host genes associated with CoVs and the prioritized repurposed drugs will provide a new sight in therapeutics discovery for severe COVID-19 patients.

19.
iScience ; 25(9): 104914, 2022 Sep 16.
Article in English | MEDLINE | ID: covidwho-2069197

ABSTRACT

The rapid spread of SARS-CoV-2 variants poses a constant threat of escape from monoclonal antibody and vaccine countermeasures. Mutations in the ACE2 receptor binding site on the surface S protein have been shown to disrupt antibody binding and prevent viral neutralization. Here, we used a directed evolution-based approach to engineer three neutralizing antibodies for enhanced binding to S protein. The engineered antibodies showed increased in vitro functional activity in terms of neutralization potency and/or breadth of neutralization against viral variants. Deep mutational scanning revealed that higher binding affinity reduces the total number of viral escape mutations. Studies in the Syrian hamster model showed two examples where the affinity-matured antibody provided superior protection compared to the parental antibody. These data suggest that monoclonal antibodies for antiviral indications would benefit from affinity maturation to reduce viral escape pathways and appropriate affinity maturation in vaccine immunization could help resist viral variation.

20.
NeuroQuantology ; 20(11):2503-2519, 2022.
Article in English | EMBASE | ID: covidwho-2067336

ABSTRACT

Even more than two years, Coronavirus Disease 2019 (COVID-19) has been emerging as a harshening name which influence the health indicator of human being by life threatening illness in all over world. It had been revealed first time in Wuhan, China, in December 2019. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the etiological sources of COVID-19. There is currently no precise treatment or vaccine against COVID-19. India is second highly condensed country in the world, where is the limited sources of earning, education as well as technology. Therefore, in the shortcoming of pharmaceutical preparation, the advanced implementation of precautions and hygienic measures will be essential to control and to minimize human transmission of the virus. In response to the rapidly escalating number of publications on the emerging disease, this review attempts to provide a timely and comprehensive review of recent development and present situation of India in view of COVID-19. It has been more than two years of this havoc, still it is not eradicated completely. We will cover the preliminary knowledge towards the epidemiology, etiology, virology, diagnosis, treatment, prognosis, and prevention of the disease in the world as well as in India. Meanwhile many questions will be arising day by day;we are expecting that this review helps in the understanding and eradication of the threatening disease as a future outcome. Copyright © 2022, Anka Publishers. All rights reserved.

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